Project Summary/Abstract Alzheimer?s disease (AD) is an extremely prevalent and severely disabling disease. Despite several decades of research, AD pathogenesis continues to be poorly understood, and we currently lack reliable biomarkers to spatiotemporally track and predict disease progression. Our overall goal is to address these challenges and develop enhanced biomarkers for diagnosing AD-pathology early and objectively tracking treatments. To that end, this proposal will utilize our highly translational monkey model of the early ?synaptic phase? of AD to assess the merits of in vivo imaging measures (from PET for synaptic density (using 11C-UCB-J) and glucose metabolism (using 18F-FDG), with structural MRI) against postmortem, state-of-the-art microscopic and histologic analysis of brain tissue, in a longitudinal study design. Our hypothesis is that PET measures, as surrogates for quantifying synaptic loss and metabolic dysfunction, will serve as early, independent predictive biomarkers for elevated AD risk and cognitive dysfunction. Our first specific aim will establish the correlation of our in vivo imaging measures with postmortem tissue markers of AD-associated pathologies in our monkey model versus age- and sex-matched control animals. Our second specific aim will map the spatiotemporal patterns of PET synaptic loss versus cerebral glucose metabolism in our monkey model versus control animals over a 12-week period. Completion of both aims will provide novel data to improve our understanding of synaptic neuropathology in AD development. Therefore, this proposal is highly responsive to the PAR-18-760. Positive findings would corroborate recent human studies investigating the role of synaptic dysfunction as a major factor for increased AD risk. Validation of in vivo imaging strategies in a relevant model system will contribute towards (i) optimizing the therapeutic window for future early AD treatments so that their efficacy can be maximized; (ii) testing mechanistic hypotheses associated with the role/blockage of synapse loss; (iii) rapidly evaluating new treatment strategies and their dose-response relationships. In summary, this project has the potential to provide key translational elements that will inform human studies evaluating in vivo markers of synaptic dysfunction.